Jiang Beibei, Shang Yile, Zhang Xiang, He Wenguang, Hua Hanju, Ye Feng, Zhou Xile, Li Yandong, Zhong Weixiang, Jiang Weiqin, Wu Guosheng
Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
College of Medicine, Zhejiang University, Hangzhou 310058, China.
Oncologist. 2025 Jun 4;30(6). doi: 10.1093/oncolo/oyaf141.
The homologous recombination (HR) system repairs DNA double-strand breaks produced by the DNA damage response, which is a complex signaling pathway consisting of the key proteins BRCA1/2 and other DNA repair proteins, such as the ATM, PALB2, BARD1, RAD51, and Fanconi anemia proteins. Mutations and epigenetic alterations in HR-related genes may lead to homologous recombination deficiency (HRD), resulting in genomic instability and contributing to the development of certain solid tumors. The biological significance and molecular mechanism of BRCA1/2 mutation-related HRD are well understood, but the relationships of other HR-related genes and their variant forms with HRD have not been sufficiently studied. These genes exhibit multiple forms of variation, including one or more HR genes, germline or somatic mutations, monoallelic or biallelic variants, and not all variants present HRD. Therefore, HRD is usually defined as HR-related gene variation, but recent studies have shown that defining it as the combined score of loss of heterozygosity, LST and TAI, known as the HRD score, can more accurately assess genomic instability. In patients with HRD, platinum-based therapy and poly ADP-ribose polymerase enzyme inhibitor (PARPi) have been shown to perform well in ovarian, breast, and prostate cancers. For gastrointestinal cancer (GI cancer), HRD has been relatively well studied in pancreatic cancer, but its role in other cancers has rarely been reported. Herein, we review the pathogenesis and predictive value of HRD, including the use of platinum drugs, PARPi, and immunotherapy, in digestive system tumors.
同源重组（HR）系统可修复由DNA损伤反应产生的DNA双链断裂，DNA损伤反应是一个复杂的信号通路，由关键蛋白BRCA1/2和其他DNA修复蛋白组成，如ATM、PALB2、BARD1、RAD51和范可尼贫血蛋白。HR相关基因的突变和表观遗传改变可能导致同源重组缺陷（HRD），从而导致基因组不稳定并促进某些实体瘤的发生。BRCA1/2突变相关HRD的生物学意义和分子机制已得到充分了解，但其他HR相关基因及其变异形式与HRD的关系尚未得到充分研究。这些基因表现出多种变异形式，包括一个或多个HR基因、种系或体细胞突变、单等位基因或双等位基因变异，并非所有变异都会导致HRD。因此，HRD通常被定义为HR相关基因变异，但最近的研究表明，将其定义为杂合性缺失、大片段基因组改变（LST）和端粒等位基因不平衡（TAI）的综合评分，即HRD评分，可以更准确地评估基因组不稳定性。在HRD患者中，铂类疗法和聚ADP核糖聚合酶抑制剂（PARPi）已被证明在卵巢癌、乳腺癌和前列腺癌中表现良好。对于胃肠道癌，HRD在胰腺癌中已有相对充分的研究，但其在其他癌症中的作用鲜有报道。在此，我们综述了HRD在消化系统肿瘤中的发病机制和预测价值，包括铂类药物、PARPi和免疫疗法的应用。
